Genetic instability plays a prominent role in biology and medicine. It is associated with diverse biological processes such as aging, developmental defects and tumorigenesis. At the same time, induction of genetic instability with ionizing radiation is used to treat cancer. Here, we report that genetic instability also has a profound effect on protein quality control. HSP90 is a chaperone that folds a subset of the proteome called clients, which are composed of proteins important for signaling, such as kinases, steroid receptors, transcription factors and enzymes. DNA-PK is one of the kinases that phosphorylates HSP90 and regulates its activity. Using conditional knockout of DNA-PK, we studied the role of DNA-PK in immune response, particularly in asthma. Knocking out DNA-PK in dendritic cells decreased asthmatic response to house dust mite and administering DNA-PK inhibitor decreased asthmatic response in mice. These findings suggest that DNA-PK activity in dendritic cells may be a target for asthma treatment.